This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human aging is associated with attenuated cutaneous vasodilation (VD) during hyperthermia due to a reduction in non-nitric oxide (NO)- and NO-dependent mechanisms. Preliminary data suggest that standard aspirin therapy for prevention of atherothrombotic disease severely attenuates reflex cutaneous vasodilation in middle-aged human skin (58[unreadable]3 years). Aspirin therapy may inhibit COX isoforms in platelets and vascular tissue, thus blocking a key enzyme involved in VD. Alternatively, platelet activation during heat stress may release substances mediating pathways contributing to VD. We will examine the roles of platelets and vascular COX on reflex VD using systemic interventions (low-dose aspirin and/or platelet inhibitor, clopidogril bisulfate) coupled with a localized examination of NOS- and COX-derived vasodilators. Hypothesis 1: Low-dose aspirin (81 mg) will attenuate reflex cutaneous vasodilation through COX-dependent mechanisms. Hypothesis 2: Specific platelet inhibition with clopidogrel bisulfate will not attenuate reflex cutaneous vasodilation. After screening subjects undergo baseline testing (no oral pharmacologics) incorporating cutaneous microdialysis (MD), whole body heating, and laser Doppler flowmetry. For the testing procedure, four intradermal microdialysis probes will be placed in the skin. Microdialysis sites are assigned drug treatments to serve as to serve as Control, nitric oxide synthase-inhibited (NOS-I), COX-inhibited (COX-I) and NOS and COX inhibited (NOS-I+COX-I). Then subjects enter the double-blind crossover design study with 81 mg of aspirin and/or 75 mg of clopidogrel bisulfate (Plavix [unreadable]). Subjects take each drug for 7 days followed by a 2 week washout before the start of the other drug. Analyses include three-way repeated measures ANOVA. PROC MIXED procedure in SAS.